bims-mitost 2019-05-05 papers

Issue of 2019–05–05
four papers selected by
Yvonne Will

Curr Atheroscler Rep. 2019 Apr 30. 21(6): 23

Diabetogenic Action of Statins: Mechanisms.

PURPOSE OF REVIEW: Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins.
RECENT FINDINGS: Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

Keywords: HMGCoA reductase inhibition and new onset diabetes; Metabolic syndrome; Statins and diabetes; Statins and new onset diabetes; Statins and risk of incident diabetes

DOI: https://doi.org/10.1007/s11883-019-0780-z

Methodist Debakey Cardiovasc J. 2019 Jan-Mar;15(1):15(1): 23-31

Statins: Then and Now.

Peter P Toth, Maciej Banach.

The discovery of statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) is a consequence of the highly targeted, arduous search for naturally occurring compounds that inhibit cholesterol biosynthesis. An enormous amount of basic scientific, genetic, and clinical research substantiated the role of lipoprotein-derived cholesterol in atherogenesis. Quantifying the impact of lipid lowering on cardiovascular event rates became an issue of utmost urgency. Although a variety of nonstatin drugs had been tested in clinical trials, they found limited utility in the clinical setting due to lack of mortality reduction or tolerability issues. As multiple prospective randomized statin trials began publishing their results, it became clear that reducing atherogenic lipoprotein burden with these drugs was highly efficacious, safe, and generally well tolerated. Statins have been shown to reduce risk for nonfatal MI, ischemic stroke, need for revascularization, and cardiovascular and all-cause mortality. They have also been shown to stabilize and even regress established atherosclerotic plaque. For the first 2 decades of their use, statin dosing was largely determined by risk-stratified low-density lipoprotein cholesterol (LDL-C) goals. More recently, there has been a transition away from LDL-C goal attainment with a focus more on cardiovascular risk and percent LDL-C reduction. Unfortunately, long-term adherence rates with statin therapy remain low and, even when used, they tend to be underdosed.

Keywords: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; atherosclerosis; cardiovascular events; lovastatin; low-density lipoprotein cholesterol; mevastatin

DOI: https://doi.org/10.14797/mdcj-15-1-23

Expert Rev Clin Pharmacol. 2019 Apr 27. 1-10

Evidence and mechanisms for statin-induced cognitive decline.

Brendan Tan, Franklin Rosenfeldt, Ruchong Ou, Con Stough.

INTRODUCTION: Statin drugs have become the most highly prescribed drugs for cardiovascular disease. However, there is disagreement as to the existence of adverse effects of statin administration on cognitive function. Therefore, it is important to better understand the effects of statins on cognition and possible mechanisms of these effects. Areas covered: We analyzed relevant studies of the relationship between cognitive performance and statin and usage. We included articles published between 2018 and 1992. We identified three randomized trials, one observational study and 66 case reports that provided credible evidence of statin-induced cognitive impairment. We also identified seven randomized trials and two observational studies reporting no significant evidence of statin-induced cognitive impairment. Expert opinion: We found methodological differences that may have contributed to the divergence of these results. Evaluation of all these studies indicated that statin-associated cognitive decline is a real entity. Likely mechanisms to explain the adverse effects include 1. Reduction of synthesis of coenzyme Q10 with consequent increasing oxidative stress and reduction of cerebral energy production; 2. Depletion of central nervous system myelin by inhibition of cholesterol synthesis. We conclude that statin-induced cognitive decline does exist, needs to be better recognized and requires more studies of prevention and treatment.

Keywords: Biological mechanisms; Coenzyme Q; HMG-CoA; cardiovascular disease; cognitive decline; side-effects; statins

DOI: https://doi.org/10.1080/17512433.2019.1606711

Drugs Aging. 2019 May 03.

Statins for Primary Prevention in Those Aged 70 Years and Older: A Critical Review of Recent Cholesterol Guidelines.

Chelsea E Hawley, John Roefaro, Daniel E Forman, Ariela R Orkaby.

The risk of atherosclerotic cardiovascular disease rises with age and remains the leading cause of death in older adults. Evidence for the use of statins for primary prevention in older adults is limited, despite the possibility that this population may derive significant clinical benefit given its increased cardiovascular risk. Until publication of the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the Management of Blood Cholesterol, and the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, guidelines for statin prescription in older adults remained unchanged despite new evidence of possible benefit in older adults. In this review, we present key updates in the 2018 and 2019 guidelines and the evidence informing these updates. We compare the discordant recommendations of the seven major North American and European guidelines on cholesterol management released in the past 5 years and highlight gaps in the literature regarding primary prevention of cardiovascular disease in older adults. As most cardiovascular events in older adults are nonfatal, we ask how clinicians should weigh the risks and benefits of continuing a statin for primary prevention in older adults. We also reframe the concept of deprescribing of statins in the older population, using the Geriatrics 5Ms framework: Mind, Mobility, Medications, Multi-complexity, and what Matters Most to older adults. A recent call from the National Institute on Aging for a statin trial focusing on older adults extends from similar concerns.

DOI: https://doi.org/10.1007/s40266-019-00673-w